New Horizons for Multiple Sclerosis Therapy: 2025 and Beyond

I am writing in regard to the recent article by Sabatino et al, “New Horizons for Multiple Sclerosis Therapy: 2025 and Beyond”1 in the August 2025 issue of the Annals of Neurology. The article is another of the authors' reviews of the various elements of the peripheral immune system that are involved in the pathogenesis of multiple sclerosis (MS). The authors summarize the roles of the various components of the immune system and how management of these cellular populations have succeeded in controlling acute inflammatory disease, but with little effect on the progressive, degenerative phases of the illness. They also discuss the possible role of viral infections in initiating the disease process and, then, proceed to hypothesize how control of the immune system and possible anti-viral vaccination could lead to a cure of the disease. Curing MS is a goal all of us wish. However, by focusing exclusively on the immune system the authors ignore a major potential component of disease susceptibility and severity, namely the increasing evidence that the central nervous systems of persons with MS are intrinsically different from those without this illness. From the observations of Professor John Prineas2 to multiple more recent articles in leading scientific journals, only some of which are cited here,3-8 it is becoming increasingly clear that changes in central nervous system function are altered in persons with MS in the absence of immune activity, potentially leading to altered susceptibility to viral infections, increased vulnerability to attack by both the innate and adaptive immune systems, and determining disease severity.9 Gut microbiomes and metabolic states are also altered in MS,10, 11 and although these aspects of MS pathology are less well defined, any “cure” for the illness must consider remediating these multiple, potentially major areas of disease susceptibility and severity. A review espousing cures for MS involving only issues of immune dysfunction provides a skewed and limited perspective on multiple facets of this complex disease that need to be addressed to achieve a true “cure.” Gary Birnbaum: Writing – original draft; conceptualization; writing – review and editing.